The modification of pharmaceutical and biologically active compounds to alter or enhance their functional properties is known in the art. Typically, prior art efforts have been directed to the production of carrier-bound drugs in which carrier molecules having selective physical properties, such as enhanced water solubility, are chemically attached to biologically active compounds. For example, Jacobson and colleagues have developed what is referred to as the “functional congener” approach to the design of carrier-bound drugs (K. A. Jacobson, in Adenosine Receptors (D.M.F. Cooper & C. Londos, eds., Receptor Biochemistry and Methodology, J. C. Venter, L. C. Harrison, eds., Alan R. Liss: New York, 1988), pp. 11:1-26). This approach involved the modification of well defined drug molecules at non-sensitive positions in a manner that retained the drug's ability to bind at its specific receptor site. In order to produce a chemically functionalized drug congener, they modified the drug molecule through the introduction of a chemical functional group which could then covalently attached to a carrier molecule. This produced a bifunctional molecule in which one portion (the “pharmacophore”) contributed its biological activity, and the second portion, or carrier, imparted its selective physical properties such as enhanced receptor attachment or water solubility. Using this approach, functional congener compounds were prepared utilizing catecholamines, adenosine receptor agonists and antagonists, and muscarinic agents.
However, recent developments in the understanding of biological mechanisms such as the binding of selective ligands to receptors and their related functions in such seemingly diverse physiological systems as the cardiovascular system, the central nervous system, and the immune system have stimulated efforts to discover alternative methods for designing biologically active compounds exhibiting properties which will selectively treat or regulate such seemingly diverse chemical systems without serious or disabling side effects. For example, adenosine receptors have been found in the cardiovascular system, in the central nervous system, and in the immune system. Accordingly, it was originally believed that the development of adenosine analogues would be effective at regulating or modifying the biological activities associated therewith. However, the ubiquitous distribution of adenosine receptors has resulted in the production of serious and disabling side effects in what were originally believed to be unrelated biological systems, thereby significantly reducing the therapeutic usefulness of adenosine analogues.
Similar interrelationships have also been discovered to exist in the mammalian immune system and in the mammalian nervous system. Over the past several decades numerous researchers have added considerable detail to the overall understanding of the mammalian immune system and its importance in maintaining overall physical health. In more recent years, similar detail has evolved in the study of the mammalian nervous system. As more and more information was developed in these seemingly independent fields of study, a number of close functional parallels began to appear between the two physiological systems. For example, both systems are concerned with the storage of information and use soluble chemicals to transmit signals between cells. Additionally, natural endogenous substances, such as hormones and transmitters, are active on the cells of both systems. Even more significantly, some common functions between the two systems are based upon similar chemical structures or markers on the surfaces of both nerve cells and immune cells. The recent discovery that the CD4 receptors targeted by the AIDS virus are present on both the T4 lymphocytes and on neurons is one of the more dramatic examples of the close relationship between the nervous system and the immune system.
Further crossing the classically imposed barriers between the fields of immunology and neurology, recent developments in the understanding of Alzheimer's disease have implicated an immunological component that may be present in this neurological disorder. It has been proposed that both the anatomical and biochemical specificity of the defects seen in Alzheimer's disease could be explained by an immunological attack on the brain blood vessels themselves with secondary involvement of neuronal, glial, or synaptic constituents contributing to the formation of senile plaques, or an immune-mediated compromise of vessels associated with an immune attack on specific neuronal, glial, or synaptic constituents (S. H. Appel, Neurobiol. Aging 7:512 (1986)).
Additionally, circumstantial evidence for an immunological component in neurological disorders is also provided by the altered suppressor cell function in aging populations, and more specifically in Alzheimer's disease (MacDonald et al., Clin. Exp. Immunol. 49:123-128 (1982); A. E. Miller, Ann. Neurol. 10:506-510 (1981); K. Stefansson in Clinical Neurology of Aging (M. L. Albert, ed., Oxford University Press, Oxford, (1984), pp. 7694) the implication of the existence of HLA regions of chromosome 6 and the GM locus of chromosome 14 in a large kindred with Alzheimer's disease (L. R. Weitkamp, Am. J. Hum. Genet. 35:443-53 (1983)), and by the altered immunological parameters in Down's syndrome, a disease whose symptoms are similar to senile dementia of the Alzheimer's type (SDAT).
Scientists in the nascent field of neuroinimunology have hypothesized that the defects in the function of brain cells (neurons) may be observed concomitantly as parallel defects or deficiencies in receptors on the cells of the immune system (such as peripheral blood immune cells). The validity of this hypothesis was recently brought to light with the aforementioned discovery of HIV infection in neurons. This neuroimmunologic theory has had significant impact because formerly almost all neuropsychiatric disorders were thought to be primarily due to factors such as genetic predisposition, mental attitudes, and/or resistance to natural environment rather than defects or deficiencies in cell function. Similarly, though the immune system has been implicated in numerous diseases ranging from infection to cancer to degenerative diseases such as Alzheimer's disease, arthritis, and aging, its relationship to cognitive function was previously unrealized.
Because the chemical interrelationship between these diverse physiological systems has been recognized only recently, prior art and medical treatments and pharmaceutical agents have focused almost exclusively on treating the individual systems alone. Thus, pharmaceutical compounds have been developed for treating or regulating the cardiovascular system or the immune system or the central nervous system with the idea of avoiding undesirable interactions in what are now known to be related physiological systems. By far the greatest amount of recent effort in the pharmaceutical and medical fields has been devoted to the treatment or regulation of the immune system alone. Numerous immunomodulating and antiviral agents have been disclosed in the art such as those described in European Patent Application Publication No. 0126813 by Simon et al., U.S. Pat. No. 4,221,909 to Simon et al., U.S. Pat. No. 4,211,794 to Kraska, and U.S. Pat. No. 4,221,910 to Giner-Sorolla. Unlike antibiotics which directly attack or destroy invading organisms such as bacteria, immunomodulating agents and more specifically immune enhancing agents are compounds which help to bolster the body's own defense mechanisms against the effects of infections. Immunomodulators either restore depressed immune function, or suppress hyperactive immune function.
Accordingly, there is a need for compounds that are bifunctional and that can interact with multiple receptors on the surface of different cell types. There is also a particular need for compounds that bypass the blood-brain barrierso that the activities of such compounds can be exerted in the central nervous system, such as for the treatment of diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), and other neurodegenerative diseases.
A number of such compounds and methods for synthesizing them are disclosed in U.S. Pat. No. 5,091,432 to Glasky, incorporated herein by this reference. This includes a number of bifunctional compounds that bypass the blood-brain barrier, particularly 4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide. Other synthetic methods for analogous compounds are those described in G. Shaw et al., “Purines, Pyrimidines, and Glyoxalines. Part XIII. Some New Unambiguous Syntheses of 5-Aminoglyoxalines and 5-Aminoglyoxaline-4-carboxamides, and a Synthesis of 5-Amino-1-p-D-ribofuranosylglyoxaline-4-carboxyamide,” J. Chem. Soc. 1959: 1648 (1959), incorporated herein by this reference, and in P. R. Birkett et al., “Synthesis and Intramolecular Cyclisation of 5-Aminoimidazolealkanoates and Their Conversion to Purine Derivatives, “Synthesis 1991 157-159 (1991), also incorporated herein by this, reference, which describes the synthesis of ethyl (9-hypoxanthinyl)alkanoates. The biosynthetic pathways for purines are also known and are described, for example, G. M. Blackburn & M. J. Gait, Nucleic Acids in Chemistry and Biology (2d ed., Oxford University Press, 1996), pp. 148152, also incorporated herein by this reference.
Although synthetic methods for these bifunctional compounds, particularly N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide, are known, there is a need for an improved synthetic method for these compounds. There is a particular need for a more efficient synthesis that provides higher yields and fewer side-reactions as well as providing a pure product.